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CTLA-4, short for Cytotoxic T-Lymphocyte-Associated protein 4 and also called CD152. The first immunecheckpoint receptor to be clinically targeted, is expressed exclusively on T cells where it primarily regulates the amplitude of the early stages of T cell activation.

Background

CD38 is a 45kDa transmembrane glycoprotein which appears to utilize the BCR signaling pathway to induce CLL cell survival and proliferation. CTLA4 expression is inversely correlated with CD38 expression in chronic lymphocytic leukemia (CLL) cells. We have shown that CTLA4 is overexpressed in low CD38-expressing CLL cells in comparison to high CD38-expressing CLL cells. In addition, CTLA4 was found to be reliable in predicting the clinical outcome in CLL patients, as higher expression of CTLA4 is associated with good clinical outcome. Moreover, the presence of CTLA4 has been correlated to increased risk and Rai stages in CLL.

In contrast to TCR and CD28-mediated signalling, very little is known about the signals induced when CTLA-4 binds its ligands CD80 or CD86 on the APC. Like CD28, the cytoplasmic domain of CTLA-4 contains a binding site for the SH2 domains of PI-3 kinase, other potential SH2 domain-binding motifs, and one SH3 domain-association sequence. There are two potential sites for tyrosine phosphorylation, Tyr201 (YVKM motif) and Tyr218 (YFIP motif), and although demonstration of tyrosine phosphorylation of the cytoplasmic domain of CTLA-4 has been difficult, the Src family tyrosine kinases Fyn, Lyn, and Lck were recently found to associate with CTLA-4 and phosphorylate both tyrosine residues. Although the cytoplasmic domain of CTLA-4 contains a binding site for PI-3 kinase, reports of PI-3 kinase association with CTLA-4 are conflicting. One study utilizing a CD8-CTLA-4 cytoplasmic tail construct found no association of PI-3 kinase following stimulation with mAb, while a conflicting study found that mAb triggering of CTLA-4 in a T cell line did lead to PI-3 kinase association and activation of kinase activity. The CTLA-4 signalling has also been shown to interfere with proximal TCR signalling by suppression of extracellular signal-regulated kinase (ERK) and Jun NH2-terminal kinase (JNK) activity.

Aberration in the expression of co-stimulatory molecules and co-inhibitory molecules can increase or decrease the risk of cancer. CTLA4 is mainly expressed on CD4+ T cells. It is a member of the CD28 receptor family and shares many features with CD28, for example, both are expressed from chromosome 2q33-34, the presence of a single disulfide-linked extracellular IgVlike domain, and their common tendency to function as dimmers. CTLA4 binds to the CD80 (B7-1) and CD86 (B7-2) ligands found on B-cells, but unlike the CD28 receptor, it has a much higher affinity for CD80 and inhibits the secondary activation of T-cells by inhibiting the phosphorylation of Akt. In addition, it has been shown that CTLA4 can also inhibit the cell cycle progression in T-cells by inhibiting the production of cyclin D3 and cyclin-dependent kinases. Concurrently, T-cells show an increase in activation and proliferation in the absence of CTLA4.

CTLA4 has been shown to be a very promising target for the treatment of many chronic immunological diseases. Together, these findings warrant further in-depth study into the role of CTLA4 in the proliferation and/or survival of CLL cells.